Ischemic heart disease is the major form of heart failure. Heart failure affects millions of people worldwide and is the leading cause of death in the United States. The most common manifestation of cardiac ischemia is chest pain (angina pectoris) which can lead to heart attack (acute myocardial infarction or AMI) and sudden death. In addition to those who exhibit clinical symptoms of ischemic heart disease, many other individuals are at high risk of developing heart disease based on indicators such as hypertension conditions, high levels of serum cholesterol and/or family history.
Myocardial ischemic disorders occur when cardiac blood flow is restricted (ischemia) and/or when the oxygen supply to heart muscle is compromised (hypoxia) such that the heart's demand for oxygen is not met. Atherosclerosis of the coronary artery is the most common cause of ischemia-associated symptoms such as angina pectoris. Ischemia and hypoxia can be transient and reversible, but can also lead to infarction. During infarction, cardiac tissue is damaged and the heart cells become permeabilized, releasing a portion of their contents to the surrounding milieu, including cardiac enzymes and other biochemical markers. These cellular markers, such as creatine kinase (CK), lactic acid dehydrogenase (LDH) enzymatic activities and creatine kinase-MB (CKMB) and troponin (I and T) and myoglobin mass levels, are then detectable in the serum.
Current diagnostic procedures generally assess the extent of cardiac tissue damage after clinical signs have appeared. At that point, however, the disease may have progressed to an extent where AMI is imminent or has already occurred. Current methods of identifying and confirming infarction require more time than is often available in emergency situations where rapid evaluation is critical for effective patient treatment and survival. Moreover, about 25% of AMI patients display atypical symptoms and many known tests result in false negatives, resulting in the unintentional discharge of about 5% of patients who have AMI (Mair J. et al., Clin. Chem. 41:1266-1272, 1995; Newby L. K. et al., Clin. Chem. 41:1263-1265, 1995). In an emergency medical facility, electrocardiography (ECG) monitoring of suspected AMI patients is the most rapid diagnostic method for detecting AMI, although it successfully detects only about half of AMI patients (Mair et al., 1995).
Electrocardiography and currently available diagnostic blood tests are generally not effective for early detection of myocardial ischemia that precedes the damage associated with AMI because the tests detect infarction-associated tissue damage. They are not effective in early detection of chronic underlying coronary artery disease and the resulting myocardial ischemia that precedes the damage associated with AMI. Currently, the only diagnostic for chronic underlying coronary artery disease is ECG monitoring during exercise stress (e.g., treadmill exercise) is generally used to confirm the clinical symptoms of angina Such stress testing is usually given after the patient has experienced symptoms and sought treatment (e.g., at an emergency medical facility). Although stress testing is sometimes used to screen asymptomatic patients, testing is costly, time-consuming and generally not amenable to routine screening of large numbers of patients. Furthermore, exercise stress test evaluations result in about 15% false negatives.
Diagnostics tests have been developed that use cardiac proteins to determine whether or not the source of the patient's chest pain is cardiac and if so, whether the patient has suffered a myocardial infarct or is suffering from unstable angina (see, e.g., U.S. Pat. Nos. 5,290,678, 5,604,105, and 5,710,008). These tests do not give an early warning for when myocardial infarct is forthcoming. Thus, a non-invasive, sensitive, and reliable point-of-care `bedside test` is needed for the early detection of cardiac ischemia, particularly for people at risk for heart disease.
In view of the need for rapid and reliable methods for detecting cardiac ischemia in the absence of symptoms, particularly for screening those at high risk of heart disease, the present invention is an early detection assay for cardiac ischemia or hypoxia.